Current Research on Endometriosis: An Interview with Dr. Brett McKinnon

Unlocking Disease Genetics: A Path to Better Understanding and Treatment of Complex Illnesses

Dr. med. Nadine Rohloff: I am very pleased to introduce Brett McKinnon from Australia and we will talk about his research in a moment. I think we should start with a little introduction, so I would like you to introduce yourself to our readers.

Dr. Brett McKinnon: Thank you very much for inviting me to speak here today. I’m Brett McKinnon from the University of Queensland in Australia. I work in the Genomics of Reproductive Disorders Laboratory at the Institute for Molecular Bioscience, and we’re mainly looking at endometriosis, and we’re doing a lot of work on genetic risk factors for endometriosis, including modeling endometriosis and the endometrium in the laboratory.

Dr. med. Nadine Rohloff: That’s great. We want to show what’s happening in research right now. Maybe we can start a little bit with how you got interested in endometriosis. How did you get interested in doing empirical research?

Dr. Brett McKinnon: That was a few years ago. I was finishing my PhD in Brisbane and looking for a postdoctoral position. I had heard about a lab in Switzerland in Bern, an excellent endometriosis lab that had a vacancy. However, when I started working there, I had never heard of endometriosis. I remember getting on the plane and reading about it for the first time and thinking, “This is such a complicated disease.” I don’t know how we’re going to research all of this. But I was lucky, we had a very dedicated lab director who was very interested in endometriosis and how to solve many problems. I started looking into it and found it really fascinating from a scientific point of view that, so little was known about this disease and there were so many areas to work in. There were so many areas where patients needed help, and so there was a lot to do for years. I started looking into it then, and I’m still doing it.

Brett McKinnon

Dr. med. Nadine Rohloff: There are still many things to discover. And since you’re in Australia, maybe you can tell us something about endometriosis care in Australia, because I think Australia is a few steps ahead of us in endometriosis care.

Dr. Brett McKinnon: I think that’s a good question. As I said, when I first started looking into endometriosis, I hadn’t heard of it in Australia. At that time, many years ago, there wasn’t a lot of awareness of this disease and, as in many other countries, it wasn’t really known by both affected patients and many frontline clinicians. It’s been a couple of years, and one of the great things that has happened in Australia recently is that the government has engaged to some extent and started to put action plans in place, which we call the National Action Plan, which focuses on endometriosis and focuses on three different pillars: more awareness, more research, and improving care. Research has increased. It takes a long time for research to really translate into benefits, but I think we’re starting to see a little bit more of that now, and that’s leading to improvements in care. I think Australia is on the right track to improving care for endometriosis patients, even though there’s still a long way to go.

Dr. med. Nadine Rohloff: It’s great that you work mainly in the lab. You also feel like you have more opportunities to push research forward. Now I want to dive a little bit deeper. You have already told us that you work in genomics. Since we also have a lot of female patients in the audience, I think it would be good if we could talk about genomics. And why are the models of endometriosis in the lab important to learn more about the disease and eventually treat it or do something to diagnose it?

Dr. Brett McKinnon: We know from studies that were done years ago, especially twin studies, that endometriosis runs in families. There is a hereditary component, and most women who have endometriosis can confirm that they have family members who have endometriosis. We know that there is a genetic component if it is hereditary. Endometriosis itself is what is known as a complex genetic disease, which simply means that there is not just one gene responsible for endometriosis, as there are many other diseases that are known to be genetic. You have a disease and a mutation, and that can lead to the disease. With endometriosis, it’s quite different. These are many small mutations that have small effects that can accumulate in certain ways and then increase susceptibility to endometriosis. We know that there is a genetic link. It is one of the main causes of the disease, but there are many different variants. We’re doing our best to figure out what those variations are, and that’s coming along. I think the next step is to understand what these variations do and how they contribute to increasing susceptibility.

Dr. med. Nadine Rohloff: I mean, that’s what makes it complicated. It’s not just one gene and then you know what happens, it’s multiple genes interacting with each other. There are a lot of pathways involved.

Dr. Brett McKinnon: That’s right. I think it’s important to understand that you don’t just have a genetic change and then get the disease. These are normal mutations that occur in everybody, and they are everywhere in the population. It’s only when they occur in the wrong combinations and many, many of them must occur in the wrong combination creating disease susceptibility, with an increased risk of getting the disease. We’re still at a stage where we don’t know what most of these genes are, but we’re starting to put some of them together.

Dr. med. Nadine Rohloff: May I ask how that is achieved?

Dr. Brett McKinnon: We don’t know the genes themselves, but only the regions of the genetic code, and that is done with very, very large sample numbers. The most recent study called the genome-wide association study, looked at all the people who have endometriosis and all the people who don’t have endometriosis. You can compare their whole genome to them and look for the more common mutations. They just compare those genomes to each other to see the differences.

Dr. med. Nadine Rohloff: What do you do in the lab when you identify regions? And how do you get your samples, for example, to study these genes further?

Dr. Brett McKinnon: The problem is that we can identify these regions, but we don’t know what they do. We have no idea why this slight change in the genetic code affects the behavior of the cells, which can lead to the development of endometriosis. That’s sort of my role in the program that we’re doing: I make models of the endometrium and endometriotic lesions in the laboratory. We are conducting a study at the local hospital, enrolling patients with endometriosis who generously provide us with samples if they agree to our plan. We take these samples to the lab and try to make small versions of the endometrium in a dish. Then we can try to understand how the cells behave based on differences in these genes and whether the behavior of these cells increases or decreases the likelihood that they will cause lesions.

Dr. med. Nadine Rohloff: Do you work mainly with endometriosis specimens obtained from patients undergoing surgery?

Dr. Brett McKinnon: Yes, that is correct. They come from patients who undergo laparoscopic surgery. During this surgical procedure, either an endometrial biopsy or a piece of the normal endometrium is taken because we believe, and many theories suggest that endometriotic lesions originate there. So, we will study those cells, but we will also take some of the cells from the lesions themselves. We have several projects where we’re looking at whether there are better treatments for endometriosis and whether they need to be customized for each individual based on their genetic background. So, if we take this tissue, we can also take the endometriotic lesions and grow small versions of the lesions in the laboratory.

Dr. med. Nadine Rohloff: Can you tell us a little bit about some of the studies you’ve done? What did you find out? What correlations did you find?

Dr. Brett McKinnon: One of the interesting studies that we’re doing right now (link to the publication), as I mentioned earlier, is that we think there’s a slight variation in the cells in the endometrium of women with endometriosis. Using these models, we took some endometrial biopsies from patients and then did a new and powerful technique called single-cell sequencing. In this, we isolate individual cells and then look at the overall gene expression in each of those individual cells. And when we do that, we can do that with great power and see exactly how each cell behaves on its own. We can do that with thousands of cells. We found that in the endometrium of women with endometriosis, there is a particular type of cell that is not as common in women without endometriosis. We discovered this cell, and we know that it changes the behavior of the cells a little bit, that they grow a little bit differently, and that they can have different adhesive properties. We believe that the presence of these cells may increase the risk of endometriosis in certain women.

Dr. med. Nadine Rohloff: Can you tell us a little bit about these cells or what cells are they?

Dr. Brett McKinnon: The endometrium is composed of two main cell types. There are epithelial cells, which we call the endometrial glands, and there are the supporting cells for these glands, which are called endometrial stromal cells. One of the important things I should mention about the endometrium is that it’s a unique tissue because it must grow every month. There are not many other tissues that have to go through this intense development every month. We believe that these endometrial stromal cells that we have found that have slightly different gene expressions are taking a slightly different direction than some of the other cells because of the process that they go through in their monthly development. They should have a blueprint in their genetic code for how they should develop from the beginning of the cycle to the end. But they tend to deviate a little bit from the path, and it only must be a small deviation, and then a series of cells emerge that can potentially contribute to the development of endometriotic lesions. These cells are shed at the end of the cycle, and when they return to the peritoneal cavity, these cells could contribute to the development of some of these lesions. I think it’s an important concept that we believe here that this is a developmental process that may not happen every cycle. It could just be that certain cycles are riskier than others. Women who have a genetic susceptibility to the disease may have more riskier cycles than other women.

Dr. med. Nadine Rohloff: This could possibly explain why retrograde menstruation is common but not everyone gets endometriosis. This could help explain some of the theories we have.

Dr. Brett McKinnon: That’s right. We believe that retrograde menstruation occurs in most women and most cycles, but lesions do not occur in most women and most cycles. So, there must be some variation. We believe that there is only a slight deviation in the way these cells develop. And if they have that deviation, the likelihood that they will cause a lesion is increased. It’s not guaranteed that they will trigger a lesion, but it’s just increased, and over the entire reproductive lifespan, the risk of that happening increases.

Dr. med. Nadine Rohloff: Is this also something that could help explain adenomyosis? For example, there is this theory of tissue damage and repair that could also cause them to behave differently.

Dr. Brett McKinnon: You see, it is very possible. We haven’t studied endometrial adenomyosis to be able to say that with certainty. But it’s the same concept that if the cells develop just a little bit differently particularly some of these stromal cells, then they could also start to form invasive areas in the uterus. But we haven’t studied adenomyosis.

Dr. med. Nadine Rohloff: It is a step-by-step process. It’s very interesting and I think it’s important to see that we must start at the beginning. Ultimately in this research, if we understand the materials, we can consider how to treat them. We need to understand the mechanism to address it.

Dr. Brett McKinnon: Yeah, I don’t think there’s been a new class of drugs for endometriosis for 30 years, I think it’s about the same. That’s because we don’t understand how the disease starts yet. If we want to find new treatments, we need to understand how the disease starts and how it progresses. We are not yet able to develop a new treatment, but we can at least assume that there are targets that we can look for now.

Dr. med. Nadine Rohloff: Absolutely. What are your future research goals? Do you have any other projects you would like to talk to us about?

Dr. Brett McKinnon: Some of the research that we’re doing right now is something that I’m very excited about. We’re trying to make small versions of those endometria that I mentioned. We get the cells from the patients. From those, we can then make what we call microorganoids, tiny little versions of their organs. They are so small that we pass them through microfluidic tubes so that they are less than a micrometer wide. Then we can put these cells in a dish and try different drugs to treat them as well. That creates the potential for drug screening. Theoretically, we could get these microorganoids from patients at the surgery, grow them in the lab, treat them with as many different new compounds as possible, and we could report back in 14 days and tell the patient which compound will help them. That’s in the future. There is still a long way to go, but we are working on it.

Dr. med. Nadine Rohloff: This is very exciting and very important. Especially in endometriosis, there could be different phenotypes. We have different theories. Maybe we are talking about several different diseases. It is important to be able to individualize.

Dr. Brett McKinnon: Exactly. The main point here is that the theory we’re really working on is that it’s not just one disease. There are all kinds of endometriosis, and trying to treat it the same way just doesn’t work. It hasn’t worked for 30 years. We can either try to figure out what kind of disease it is, and that’s what we’re working on in a project, or we can come at it from the other side and just say, “We don’t know what kind it is exactly, but we’re going to try all these different drugs and tell you which one is best for the disease you actually have.”

Dr. med. Nadine Rohloff: Well, I think we must do both, because one takes a long time, and you must be able to help patients sooner. I mean, that’s, I think, very exciting. Do you have anything that you need? For example, patients. Do you need something, more participants? How can people support that? Because I think that’s very exciting.

Dr. Brett McKinnon: Everything starts with the patient. I think we realize, first and foremost, how important it is that patients are involved and that they have a say in what we do. I think it’s very important and very useful for us that patients talk about the disease and raise awareness. Things like this interview make sure that the disease is in the public eye and that people do that. That’s absolutely an important point. And any opportunity to contribute to research, even just participating in the research projects that are out there, is helpful to us as well. I would really encourage people to participate in those two ways if they can.

Dr. med. Nadine Rohloff: I think that’s very exciting. I think some people want to dive a little deeper into research and what you are doing at the molecular level is phenomenal work. Do you have anything that you would like to share with us?

Dr. Brett McKinnon: I have to say, it’s a long research process. It’s not always the answer people want to hear, but it’s important to get all the research right. We must take it step by step. But if we look back to where we came from, we can see that we are moving forward at least step by step. From the initial idea and what you’re trying to develop, to collecting samples and generating data, to doing experiments and moving on to the next step, there’s a lot of work to be done. It’s a long process, but I think it’s the right way to go about things.

Dr. med. Nadine Rohloff: I think the silver lining is that there’s a lot more happening today than there was five years ago, and it’s increasing. There’s more individual research being done. I think we will be faster every year.

Dr. Brett McKinnon: I think once you reach a critical mass and people start talking about it more, people become more aware, and funders become aware because of the lobbying that takes place. That helps a lot with research. Then when there is more awareness and more funding, the research can build on the last research, and there is a snowball effect, and things move faster and faster once the critical mass is reached.

Dr. med. Nadine Rohloff: You presented your studies at the World Congress on Endometriosis, where we were. I have the feeling that there is a lot of research going on in the laboratories. You’re going to find some things that drugs can target, and new therapies can be developed for. I think it’s important to show that as well because from the patient’s perspective, you can feel that no new drugs are coming to market. It can feel like nothing is happening, but something is happening, but we must do the groundwork before we can see it.

Dr. Brett McKinnon: Yes. If the basics aren’t right, all the other endpoints, the things that happen later, won’t work anyway. We must get the basics right. I think we are on the right track.

Dr. med. Nadine Rohloff: A lot has happened, and worldwide we see that all these laboratories are working on it. I think we can be very hopeful about the future. I would like to thank you for this interesting conversation. All the best for the future.

Dr. med. Nadine Rohloff